The Moderating Effects of Genetic Variations on Changes in Physical Activity Level and Cardiorespiratory Fitness in Response to a Life-Style Intervention: A Randomized Controlled Trial

Objective Prior studies identified single nucleotide polymorphisms (SNPs) associated with physical activity (PA) level in a natural environment and intervention study: rs978656-DNAPTP6, rs10887741-PAPSS2, rs7279064-C18orf2, and rs6265-BDNF. Using the four SNPs' polygenic score (PGS), we examined whether PGS moderates a life-style intervention's effect on changes in PA level and cardiorespiratory fitness (CRF). Methods This is a secondary analysis of Look AHEAD, a multicenter randomized controlled trial designed to test the health benefits of a life-style intervention among 2675 participants with overweight/obesity and type 2 diabetes (ages, 45-76 years). Using linear mixed-effects models, level of PA (Paffenbarger PA questionnaire) and treadmill-Assessed CRF were each regressed on four SNPs' PGS, study time (baseline, year 1, and year 4), intervention arm, and interactions between the three. Models adjusted for age, sex, body mass index, ancestry principal components (population stratification), and study sites, with Bonferroni corrections for multiple testing (α <.005). Effect modification by age was examined. Results PGS was not predictive of change in CRF or PA level in response to intervention. In analyses without PGS by intervention by time, the relationships between PGS and PA phenotypes were modified by age (p interaction =.048 for CRF and.058 for PA), such that a 1-unit increase in PGS was associated with 24 kcal · wk-1 more in moderate-intensity PA and 0.004 MET higher CRF only among older groups (age >55 years for CRF, >60 years for PA level). Conclusions The effects of the intervention on PA and CRF were not moderated by the four SNPs. Future studies with extended SNP list should confirm the findings on effect modification by age.